TEM-1 as a novel regulator of renal and gastric barrier function
Prof. Dr. Berend Isermann
Prof. Dr. Michael Naumann
Diabetic nephropathy (dNP), now the most common cause of chronic renal disease, is characterized by dysfunctional barriers in the glomerular and tubular compartments. A common cell type found in both renal compartments are pericytes, which interact with epithelial (EpiC) and endothelial (EndoC) cells. Maladaptive pericyte activation impairs barrier function and promotes kidney fibrosis, a common final pathway in kidney damage. Targeting pericyte function may allow protection of both renal compartments. However, specific strategies to target pericytes are currently lacking. TEM1 (tumor endothelial marker 1, CD248, or endosialin) is a protein expressed by pericytes in various organs, including the kidney and the stomach. Expression of TEM1 is high during development in tumors and during inflammatory diseases. In a clinical study low TEM1 expression by cancer associated fibroblast correlates with increased survival of gastric cancer patients. However, the mechanisms underlying TEM1-dependent effects remain poorly defined. In preliminary cooperative work (Project 1, Project 7) we (1) analyzed expression of TEM1 in gastric tissue and (2) established a role of TEM1 in renal pericytes in the context of dNP. Based on preliminary results we hypothesize that pericyte derived TEM1 co-ordinately regulates barrier function in chronic diseases. Specifically, we wish to (1) define the molecular mechanism and functional consequences of intracellular signaling via TEM1 between pericytes and barrier-defining epithelial cells, (2) conduct a structure function analyses of TEM1 to identify the molecular structures required for barrier regulation, and (3) determine whether modulating TEM1 function allows to rescue epithelial cell and thus barrier function. Two PhD students jointly address these questions in the context of intestinal (Akshay Malhotra) or renal (Shruthi Krishnan) barriers. This project is at the core of the RTG2408, providing key technologies for in vitro barrier assays, microfluidics, and organoid culture.
Proposed function and approach to study TEM-1 at physiological barriers
(A) TEM-1 expressing cells in the kidney (blue; mesangial cells, top, and peritubular pericytes, bottom) interact with endothelial cells (red), podocytes (yellow, top), and tubular cells (yellow, bottom). (B) In the stomach fibroblasts (blue) express TEM1 and modulate epithelial cell (yellow) dedifferentiation and acquisition of a malignant phenotype (orange/red, left). TEM1 may in addition modulate trans-endothelial migration and escape of malignant epithelial cells (right). (C) We aim to decipher the role of TEM-1 for physiological barrier function, focusing on TGFβ-signaling, ER-stress (UPR: unfolded protein response), and PI3K/mTOR signaling.